Dysregulation of protein modification by ISG15 results in brain cell injury
- Kenneth J. Ritchie1,
- Michael P. Malakhov1,
- Christopher J. Hetherington1,
- Liming Zhou1,
- Marie-Terese Little1,
- Oxana A. Malakhova1,
- Jack C. Sipe1,
- Stuart H. Orkin2, and
- Dong-Er Zhang1,3
- 1Department of Molecular and Experimental Medicine, MEM-L51, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA; 2Division of Hematology-Oncology, Children's Hospital and Dana Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA
Abstract
UBP43 (USP18) is a protease that removes the ubiquitin-like modifier ISG15 from conjugated proteins. Here we present the first report of dysregulation of protein ISG15 modification by the generation of UBP43 knockout mice. In the absence of UBP43, brain tissue showed an elevated level of ISG15 conjugates, and cellular necrosis was evident in the ependyma. Such disruption of the blood–brain barrier resulted in severe neurologic disorders. These results demonstrate that UBP43 plays a critical role in maintaining the homeostatic balance of ISG15-conjugated protein, and that regulation of cellular levels of ISG15 protein modification is essential for brain cell function.
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Footnotes
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↵3 Corresponding author.
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E-MAIL dzhang{at}scripps.edu; FAX 858-784-9593.
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1010202.
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- Received May 28, 2002.
- Accepted July 12, 2002.
- Cold Spring Harbor Laboratory Press
